Review
Genetic therapies for inherited neuromuscular disorders

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Summary

Inherited neuromuscular disorders encompass a broad group of genetic conditions, and the discovery of these underlying genes has expanded greatly in the past three decades. The discovery of such genes has enabled more precise diagnosis of these disorders and the development of specific therapeutic approaches that target the genetic basis and pathophysiological pathways. Such translational research has led to the approval of two genetic therapies by the US Food and Drug Administration: eteplirsen for Duchenne muscular dystrophy and nusinersen for spinal muscular atrophy, which are both antisense oligonucleotides that modify pre-mRNA splicing. In this Review we aim to discuss new genetic therapies and ongoing clinical trials for Duchenne muscular dystrophy, spinal muscular atrophy, and other less common childhood neuromuscular disorders.

Introduction

Duchenne muscular dystrophy and spinal muscular atrophy are the most common debilitating neuromuscular disorders affecting children. The understanding of their genetic basis and knowledge about disease-specific complications has led to substantial improvement of the anticipatory care and survival of affected children in the past two decades1, 2, 3, 4 and, more recently, to the advent of experimental therapeutic approaches.

The development of such therapeutic approaches can be categorised into two broad strategies. The first strategy, initiated in the late 2000s, relates to the correction of mutant RNA processing, using either antisense oligonucleotides or small molecules that can modify mutant RNA splicing.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 A conceptually separate but related approach makes use of drugs that alter the translation of mutant mRNA by inducing a partial readthrough of non-sense mutations.17 The second strategy involves the use of adeno-associated viruses (AAVs) to deliver a functional or partially functional gene copy to the affected cells and tissues.

These new therapies are rapidly changing the management of these neuromuscular diseases. Although more research is needed to understand the long-term effects of these interventions, there is optimism that the clinically meaningful, positive early effects of some of these therapies will help to delay disease progression for these patients. Here, we review the most clinically significant therapeutic advances for these disorders and summarise ongoing trials in the field (table).

Section snippets

Duchenne muscular dystrophy

The X-linked recessive disorder Duchenne muscular dystrophy is caused by mutations in the DMD gene, which is located on the short arm of chromosome X and encodes dystrophin, a protein located under the plasma membrane (sarcolemma) of muscle fibres where it helps to preserve the structural integrity of muscle fibres. The most common mutations, affecting approximately 65% of boys with Duchenne muscular dystrophy, are out-of-frame deletions removing one or more exons. Out-of-frame duplications are

Spinal muscular atrophy

Spinal muscular atrophy is a motor neuron disease characterised by generalised muscle atrophy and weakness. It is caused by the dysfunction and eventual death of motor neurons in the ventral horn of the spinal cord, as a result of deletions in 95% of cases, but also other rare mutations of the SMN1 gene on chromosome 5q13, which encodes the survival motor neuron (SMN) protein.39, 40, 41 The estimated incidence of spinal muscular atrophy is one in 10 000 livebirths, with a carrier frequency of

Becker muscular dystrophy

In a similar effort to treat Becker muscular dystrophy, an AAV vector has been designed to deliver FS344, which encodes follistatin, a potent myostatin antagonist that inhibits muscle growth and differentiation. Preclinical studies with this vector in dystrophic animals resulted in increased muscle mass and strength.60, 61 In a proof-of-principle clinical trial (NCT01519349; table), 15 adult patients with Becker muscular dystrophy received an intramuscular injection of the gene therapy directly

Limb girdle muscular dystrophy type 2E

Limb girdle muscular dystrophies (LGMDs) are a class of genetic disorders affecting the musculoskeletal system. LGMD type 2E (LGMD2E) represents one of the most severe forms of LGMD, with an incidence of one in 200 000 to 1 in 350 000.64 In this disease, mutations in the SGCB gene lead to loss of functional β-sarcoglycan, with concurrent loss of other structural components of the dystrophin-associated protein complex, which are involved in stablising the sarcolemma.65, 66 The loss of one of the

Giant axonal neuropathy

Giant axonal neuropathy is an autosomal recessive, neurodegenerative disorder, characterised by abnormally large and dysfunctional axons with disordered microtubules and intermediate filaments. The disease is caused by loss-of-function mutations in the GAN gene encoding gigaxonin, which plays a major role in the maintenance of orderly and functional intermediate filament architecture, essential for axonal function. The disease progressively affects the sensory and motor nerves of the peripheral

X-linked myotubular myopathy

X-linked myotubular myopathy (XLMTM) is a neuromuscular disorder caused by mutations in the MTM1 gene, which encodes myotubularin. This protein plays an important role in the development, maintenance, and function of skeletal muscle cells. XLMTM is a rare condition (approximately one in 50 000 male births) characterised by profound muscle weakness, respiratory failure, and early death.74, 75 Several studies in animal models of XLMTM have shown that a single administration of an AAV8 vector

Conclusions

In the past decade, genetic therapies for neuromuscular disorders have advanced substantially, particularly for Duchenne muscular dystrophy and spinal muscular atrophy. The knowledge of the genetic basis of these two conditions, and advances in the use of small molecules, antisense oligonucleotides, and AAV gene therapy have produced remarkable results, especially with spinal muscular atrophy. However, these results also raise several issues that require urgent consideration. For example, it is

Search strategy and selection criteria

We searched PubMed, MEDLINE, and ClinicalTrials.gov for articles and clinical trial records in English, and also searched the references from relevant articles. Relevant reports and briefing documents from the US Food and Drug Administration, European Medicines Agency, and pharmaceutical companies were also included. The most common search terms were “Duchenne muscular dystrophy”, “Becker muscular dystrophy”, “spinal muscular atrophy”, “antisense oligonucleotides”, “nonsense mutations”,

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